Does the enterolactone (ENL) affect fatty acid transporters and lipid metabolism in liver?

Nutrition & Metabolism - Tập 14 - Trang 1-10 - 2017
Krzysztof Drygalski1, Klaudia Berk1, Tomasz Charytoniuk1, Nicoletta Iłowska1, Bartłomiej Łukaszuk1, Adrian Chabowski1, Karolina Konstantynowicz-Nowicka1
1Department of Physiology, Medical University of Bialystok, Białystok, Poland

Tóm tắt

NAFLD as a result of inappropriate diet and obesity, may progress to sever conditions such as: type 2 diabetes mellitus or steatohepatitis, and has recently become a prevalent topic of numerous investigations. Due to its dangerous aftermaths, finding new substances, such as polyphenols and their derivatives, which might reduce liver steatosis is the main target of research into NAFLD treatment. Hence, the aim of the present study was to evaluate the effect(s) of enterolactone (ENL), a metabolite of secoisolariciresinol (SECO), on lipid metabolism together with changes in the expression of fatty acid transporters in fatty liver. The experiments were conducted on HepG2 cells incubated with either ENL and/or palmitic acid during 16 h exposure. The expression of selected fatty acid transport proteins: FATP2, FATP5, CD36, FABPpm, ABCA1, MTP, ACBP and L-FABP, as well as the proteins directly involved in lipogenesis (FAS), oxidation pathway (CPT 1), and lipid metabolism (PPARα, LXR, SREBP1c, pAMPK) was estimated by Western Blot. Intra and extracellular lipid contents were assessed by Gas-Liquid Chromatography. The data was analyzed with two-way analysis of variance (ANOVA), and results were considered to be statistically significant at p ≤ 0.05. ENL stimulated extracellular efflux of free fatty acids (FFA) and triacylglicerols (TAG) to the medium, while, it had no influence on FATP-family mediated intracellular fatty acid uptake. Moreover, ENL decreased the expression of CPT 1, pAMPK, PPARα, increased SREBP1c and had no effect on LXR, and FAS content. The findings of our study demonstrate that ENL had opposite effect on liver steatosis in comparison with other polyphenols what suggests that it may be an inactive metabolite. ENL did not affect significantly the intracellular accumulation of FFA, DAG and TAG, yet it promoted their extracellular efflux. Furthermore, it inhibited ß-oxydation and intracellular lipid metabolism what may contribute to the progression of NAFLD.

Tài liệu tham khảo

Oddy WH, Herbison CE, Jacoby P, Ambrosini GL, O’Sullivan TA, Ayonrinde OT, et al. The Western Dietary Pattern Is Prospectively Associated With Nonalcoholic Fatty Liver Disease in Adolescence.Am. J. Gastroenterol. [Internet]. 2013 [cited 2017 May 26];108:778–785. Available from: http://www.nature.com/doifinder/10.1038/ajg.2013.95 Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment. Pharmacol. Ther. [Internet]. 2011 [cited 2017 may 26];34:274–85. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21623852 . Vos MB, Abrams Sh, Barlow Se, Caprio S, Daniels Sr, Kohli R, et al. NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: Recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). J. Pediatr. Gastroenterol. Nutr. [Internet]. 2017 [cited 2017 May 26];64:319–334. Available from: http://insights.ovid.com/crossref?an=00005176-201702000-00028 Sanyal AJ. Mechanisms of Disease: pathogenesis of nonalcoholic fatty liver disease. Nat. Clin. Pract. Gastroenterol. Hepatol. [Internet]. 2005 [cited 2017 may 26];2:46–53. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16265100 . Leclercq IA, Da Silva Morais A, Schroyen B, Van Hul N, Geerts A. Insulin resistance in hepatocytes and sinusoidal liver cells: Mechanisms and consequences. J. Hepatol. [Internet]. 2007 [cited 2017 may 26];47:142–156. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17512085 . Glatz JFC, Luiken JJFP, Bonen A. Membrane Fatty Acid Transporters as Regulators of Lipid Metabolism: Implications for Metabolic Disease. Physiol. Rev. [Internet]. 2010 [cited 2017 may 26];90:367–417. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20086080 . Krammer J, Digel M, Ehehalt F, Stremmel W, Füllekrug J, Ehehalt R. Overexpression of CD36 and acyl-CoA synthetases FATP2, FATP4 and ACSL1 increases fatty acid uptake in human hepatoma cells. Int. J. Med. Sci. [Internet]. 2011 [cited 2017 may 26];8:599–614. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22022213 . Chen X, Iqbal N, Boden G. The effects of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects. J. Clin. Invest. [Internet]. American Society for Clinical Investigation; 1999 [cited 2017 may 26];103:365–372. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9927497 . Michelotti GA, Machado M V., Diehl AM. NAFLD, NASH and liver cancer. Nat. Rev. Gastroenterol Hepatol. [Internet]. 2013 [cited 2017 May 26];10:656–665. Available from: http://www.nature.com/doifinder/10.1038/nrgastro.2013.183 Charytoniuk T, Drygalski K, Konstantynowicz-Nowicka K, Berk K, Chabowski A.Alternative treatment methods attenuate the development of NAFLD: A review of resveratrol molecular mechanisms and clinical trials. Nutrition [Internet]. 2017 [cited 2017 May 26];34:108–117. Available from: http://www.sciencedirect.com/science/article/pii/S0899900716302076 Zhou F, Furuhashi K, Son MJ, Toyozaki M, Yoshizawa F, Miura Y, et al. Antidiabetic effect of enterolactone in cultured muscle cells and in type 2 diabetic model db/db mice. Cytotechnology [Internet]. 2016 [cited 2017 May 26]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/27000262 . Chikara S, Lindsey K, Borowicz P, Christofidou-Solomidou M, Reindl KM. Enterolactone alters FAK-Src signaling and suppresses migration and invasion of lung cancer cell lines. BMC Complement Altern. Med. [Internet]. BioMed Central; 2017 [cited 2017 may 26];17:30. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28068967 . Thompson LU, Boucher BA, Liu Z, Cotterchio M, Kreiger N. Phytoestrogen Content of Foods Consumed in Canada, Including Isoflavones, Lignans, and Coumestan. Nutr. Cancer [Internet]. 2006 [cited 2017 may 26];54:184–201. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16898863 . Adlercreutz H. Lignans and Human Health. Crit. Rev. Clin. Lab. Sci. [Internet]. 2007 [cited 2017 may 26];44:483–525. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17943494 . Hu C, Yuan Y V., Kitts DD. Antioxidant activities of the flaxseed lignan secoisolariciresinol diglucoside, its aglycone secoisolariciresinol and the mammalian lignans enterodiol and enterolactone in vitro. Food Chem. Toxicol. [Internet]. 2007 [cited 2017 may 26];45:2219–2227. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17624649 . Annika I. Smeds, Patrik C. Eklund, Rainer E. Sjöholm, Stefan M. Willför, Sansei Nishibe, Takeshi Deyama and, et al. Quantification of a Broad Spectrum of Lignans in Cereals, Oilseeds, and Nuts. American Chemical Society; 2007 [cited 2017 May 26]; Available from: http://pubs.acs.org/doi/abs/10.1021/jf0629134 Konstantynowicz-Nowicka K, Harasim E, Baranowski M, Chabowski A. New Evidence for the Role of Ceramide in the Development of Hepatic Insulin Resistance. Cowart A, editor. PLoS One [Internet]. 2015 [cited 2017 may 26];10:e0116858. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25635851 . FOLCH J, LEES M, SLOANE STANLEY GH. A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. [Internet]. 1957 [cited 2017 may 26];226:497–509. Available from: http://www.ncbi.nlm.nih.gov/pubmed/13428781 . van der Vusse GJ, Roemen TH, Reneman RS. Assessment of fatty acids in dog left ventricular myocardium. Biochim. Biophys. Acta [Internet]. 1980 [cited 2017 may 26];617:347–349. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7357024 . Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L, American Association for the Study of Liver Diseases, United States Food and Drug Administration. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: Findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop. Hepatology [Internet]. 2015 [cited 2017 May 26];61:1392–405. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25557690 Clavel T, Doré J, Blaut M. Bioavailability of lignans in human subjects. Nutrition Research Reviews. 2006 19 (02) pp: 187–196. Bolvig A, Kyrø C, Nørskov N, Eriksen A, Christensen J, Tjønneland A, et al. Use of antibiotics is associated with lower enterolactone plasma concentration. Molecular Nutri Food Res. 2016;60(12):2712–21. Ehehalt R, Füllekrug J, Pohl J, Ring A, Herrmann T, Stremmel W. Translocation of long chain fatty acids across the plasma membrane – lipid rafts and fatty acid transport proteins. Mol. Cell. Biochem. [Internet]. 2006 [cited 2017 may 26];284:135–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16477381 . Kitts DD, Yuan Y V, Wijewickreme AN, Thompson LU. Antioxidant activity of the flaxseed lignan secoisolariciresinol diglycoside and its mammalian lignan metabolites enterodiol and enterolactone. Mol. Cell. Biochem. [Internet]. 1999 [cited 2017 may 26];202:91–100. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10705999 . McIntosh AL, Atshaves BP, Landrock D, Landrock KK, Martin GG, Storey SM, et al. Liver fatty acid binding protein gene-ablation exacerbates weight gain in high-fat fed female mice. Lipids [Internet]. NIH Public Access; 2013 [cited 2017 may 26];48:435–48. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23539345 . Holmes RS, S. R. Comparative Studies of Vertebrate Platelet Glycoprotein 4 (CD36). Biomolecules [Internet]. Molecular Diversity Preserv Int; 2012 [cited 2017 May 26];2:389–414. Available from: http://www.mdpi.com/2218-273X/2/3/389/ Kersten S. Integrated physiology and systems biology of PPARα. Mol. Metab. [Internet]. 2014 [cited 2017 may 26];3:354–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24944896 . Wang G, Bonkovsky HL, de Lemos A, Burczynski FJ. Recent insights into the biological functions of liver fatty acid binding protein 1. J. Lipid Res. [Internet]. 2015 [cited 2017 may 26];56:2238–2247. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26443794 . Harasim-Symbor E, Konstantynowicz-Nowicka K, Chabowski A. Additive effects of dexamethasone and palmitate on hepatic lipid accumulation and secretion. J. Mol. Endocrinol. [Internet]. 2016 [cited 2017 may 26];57:261–73. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27707773 . Yancey PG, Bortnick AE, Kellner-Weibel G, de la Llera-Moya M, Phillips MC, Rothblat GH. Importance of Different Pathways of Cellular Cholesterol Efflux. Arterioscler. Thromb. Vasc. Biol. [Internet]. 2003 [cited 2017 may 26];23:712–719. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12615688 . Iqbal J, Parks JS, Hussain MM. Lipid absorption defects in intestine-specific microsomal triglyceride transfer protein and ATP-binding cassette transporter A1-deficient mice. J. Biol. Chem. [Internet]. American Society for Biochemistry and Molecular Biology; 2013 [cited 2017 may 26];288:30432–44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24019513 . Tominaga S, Nishi K, Nishimoto S, Akiyama K, Yamauchi S, Sugahara T. (-)-Secoisolariciresinol attenuates high-fat diet-induced obesity in C57BL/6 mice. Food Funct. [Internet]. 2012 [cited 2017 may 26];3:76–82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22030618. Huang C-Z, Tung Y-T, Hsia S-M, Wu C-H, Yen G-C. The hepatoprotective effect of Phyllanthus emblica L. fruit on high fat diet-induced non-alcoholic fatty liver disease (NAFLD) in SD rats. Food Funct. [Internet]. 2017 [cited 2017 may 26];8:842–50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28128372 . Moon Y-A, Hammer RE, Horton JD. Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice. J. Lipid Res. [Internet]. American Society for Biochemistry and Molecular Biology; 2009 [cited 2017 may 26];50:412–423. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18838740 . Consitt LA, Bell JA, Houmard JA. Intramuscular lipid metabolism, insulin action, and obesity. IUBMB Life. NIH Public Access; 2009 [cited 2017 may 26];61:47–55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18839419 . Winder WW, Hardie DG. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am. J. Physiol. [Internet]. 1999 [cited 2017 may 26];277:E1–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10409121 . Lu K-L, Xu W-N, Wang L-N, Zhang D-D, Zhang C-N, Liu W-B. Hepatic β-Oxidation and Regulation of Carnitine Palmitoyltransferase (CPT) I in Blunt Snout Bream Megalobrama amblycephala Fed a High Fat Diet. Zhang Y, editor. PLoS One [Internet]. 2014 [cited 2017 may 26];9:e93135. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24676148 . Kohjima M, Enjoji M, Higuchi N, Kato M, Kotoh K, Yoshimoto T, et al. Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. Int. J. Mol. Med. [Internet]. 2007 [cited 2017 may 26];20:351–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17671740 . Monsalve FA, Pyarasani RD, Delgado-Lopez F, Moore-Carrasco R. Peroxisome Proliferator-Activated Receptor Targets for the Treatment of Metabolic Diseases. Mediators Inflamm. [Internet]. 2013 [cited 2017 may 26];2013:1–18. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23781121 . Souza-Mello V, Gregório BM, Cardoso-de-Lemos FS, de Carvalho L, Aguila MB, Mandarim-de-Lacerda CA. Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet. Clin. Sci. [Internet]. 2010 [cited 2017 may 26];119:239–50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20415664 . Schultz A, Neil D, Aguila M, Mandarim-de-Lacerda C. Hepatic Adverse Effects of Fructose Consumption Independent of Overweight/Obesity. Int. J. Mol. Sci. [Internet]. 2013 [cited 2017 may 26];14:21873–86. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24196354 . Pan A, Sun J, Chen Y, Ye X Li H, Yu Z, et al. Effects of a flaxseed-derived lignan supplement in type 2 diabetic patients: a randomized, double-blind, cross-over trial. PLoS One [Internet]. Public Library of Science; 2007 [cited 2017 may 26];2:e1148. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17987126. Higuchi N, Kato M, Shundo Y, Tajiri H, Tanaka M, Yamashita N, et al. Liver X receptor in cooperation with SREBP-1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease. Hepatol. Res. [Internet]. 2008 [cited 2017 may 26];38:1122–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18684130 . Zhu M, Harshbarger WD, Robles O, Krysiak J, Hull KG, Cho SW, et al. A strategy for dual inhibition of the proteasome and fatty acid synthase with belactosin C-orlistat hybrids. Bioorg. Med. Chem. [Internet]. 2017 [cited 2017 may 26];25:2901–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28236510 . Porras D, Nistal E, Martínez-Flórez S, Pisonero-Vaquero S, Olcoz JL, Jover R, et al. Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation. Free Radic. Biol. Med. [Internet]. 2017 [cited 2017 may 26];102:188–202. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27890642 . Leong PK, Ko KM. Schisandrin B: A Double-Edged Sword in Nonalcoholic Fatty Liver Disease. Oxid. Med. Cell. Longev. [Internet]. Hindawi Publishing Corporation; 2016 [cited 2017 May 26];2016:1–13. Available from: https://www.hindawi.com/journals/omcl/2016/6171658/ Pan S-Y, Dong H, Guo B, Zhang Y, Yu Z-L, Fong W-F, et al. Effective kinetics of schisandrin B on serum/hepatic triglyceride and total cholesterol levels in mice with and without the influence of fenofibrate. Naunyn. Schmiedebergs. Arch. Pharmacol. [Internet]. 2011 [cited 2017 may 26];383:585–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21523558.